1. Field of the Invention (Technical Field)
The present invention relates to piperazine and ketopiperazine molecules with three biologically relevant pendant groups that bind to one or more melanocortin receptors and are agonists, antagonists or mixed agonist-antagonists.
2. Description of Related Art
Note that here and elsewhere the specification refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of tissues.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma and melanin-associated disorders. Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other food intake and metabolism-related purposes and disorders. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used as agents for treatment of sexual dysfunction, including male erectile dysfunction. Other melanocortin receptor-specific compounds, such as MC1-R agonists, can be used as tanning agents to increase melanin production. Compounds specific for MC1-R, MC3-R and MC5-R may be useful in regulation of inflammatory processes.
WO 02/085925, “Melanocortin Receptor Ligands”, to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, methods to synthesize piperazine structures, or methods to synthesize optically pure structures, and further does not disclose structures with a pendant group consisting of a single D-Phe residue, or a derivative or homolog thereof, optionally with an amine capping group.
There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as compounds that are either agonists or antagonists for specific melanocortin receptors. High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.